Advertisement

Chemical Papers

, Volume 73, Issue 1, pp 39–46 | Cite as

Improved protocol for synthesis of N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholin-4-ylpropoxy) quinazolin-4-amine (gefitinib)

  • Pawan KumarEmail author
  • Muhammad Taufiq F. Mazlee
  • Muhammad K. Abdul Wahab
  • Chandra Kant Belwal
  • Ramesh Kumar
  • Shahnawaz Sajid
Original Paper
  • 64 Downloads

Abstract

An improved three-step process for the synthesis of gefitinib from readily available starting material is discussed in this protocol. The protocol is based on the synthesis, isolation, characterization of novel intermediates and their application in the alkylation step for the synthesis of gefitinib. Excellent results were achieved over the conventional synthetic methodologies. Isolation of these intermediates were effective in replacing high boiling solvent with low boiling solvent(s) but also in eliminating base from the reaction. These conditions led to effective elimination of all the prior art reported impurities. This high-yielding process is cost-effective with isolable and stable intermediates. These intermediates were characterized using NMR, mass spectroscopy, DSC and XRPD analyses.

Keywords

Gefitinib Iressa Alkali metal salts O-Alkylation Novel intermediate Improved protocol 

Supplementary material

11696_2018_564_MOESM1_ESM.pdf (605 kb)
Supplementary material 1 (PDF 605 kb)

References

  1. Abouzid K, Showman S (2008) Design, synthesis and in vitro antitumor activity of 4-aminoquinoline and 4-aminoquinazoline derivatives targeting EGFR tyrosine kinase. Bioorg Med Chem 16:7543–7551.  https://doi.org/10.1016/j.bmc.2008.07.038 CrossRefGoogle Scholar
  2. Armarego WF, Chai CLL (2012) Purification of laboratory chemicals, 7th edn. Butterworth-Heinemann, OxfordGoogle Scholar
  3. Barker AJ (1993) Quinazoline Derivatives. European Patent 0566226Google Scholar
  4. Barker A, Brown DS (1996) Quinazoline Derivatives European Patent 060285B1Google Scholar
  5. Bridges AJ (2001) Chemical inhibitors of protein kinases. Chem Rev 101(8):2541–2572.  https://doi.org/10.1021/cr000250y CrossRefGoogle Scholar
  6. Ciardiello F, Vita FD, Orditura M, Placido SD, Tortora G (2005) Epidermal growth factor receptor tyrosine kinase inhibitors in late stage clinical trials. Expert Opin Emerg Drugs 8:501–514.  https://doi.org/10.1517/14728214.8.2.501 CrossRefGoogle Scholar
  7. Feng L, Feng Y, Meng Q, Zhiming L, Wang Q, Tao F (2007) An efficient construction of quinazolin-4(3H)-ones under microwave irradiation. Arch Org Chem 1:40–50.  https://doi.org/10.3998/ark.5550190.0008.105 Google Scholar
  8. Gibson HK (1998) Quinazoline derivatives. US Patent5770599Google Scholar
  9. Kang SK, Lee SW, Woo D, Sim J, Suh YG (2017) Practical & efficient synthesis of gefitinib through selective O-alkylation: a novel concept for a transient protection group. Synth Commun 47(21):1990–1998.  https://doi.org/10.1080/00397911.2017.1359627 CrossRefGoogle Scholar
  10. Pandey A, Volkots DL, Seroogy MJ, Rose WJ (2002) Identification of orally active, potent and selective 4-piperazinylquinazolines as antagonists of the platelet-derived growth factor receptor tyrosine kinase family. J Med Chem 45(17):3772–3793.  https://doi.org/10.1021/jm020143r CrossRefGoogle Scholar
  11. Schnur RC, Arnold LD (1998) Alkynyl and azido-substituted 4-anilinoquinazolines. US Patent 5747498Google Scholar
  12. Wang JQ, Gao M, Miller KD, Sledge GW, Zheng QH (2006) Synthesis of [11C] Iressa as a new potential PET cancer imaging agent for epidermal growth factor receptor tyrosine kinase. Bioorg Med Chem Lett 16:4102–4106.  https://doi.org/10.1016/j.bmcl.2006.04.080 CrossRefGoogle Scholar
  13. William RFG, Kay B, Oliver C, Matthew E, Martin FJ, Kirsty M, Raquel RS, Yvonne S, Paul S, Brain W (2017) The development of a Dimroth rearrangement route to AZD8931. Org Process Res Dev 21(3):336–345.  https://doi.org/10.1021/acs.oprd.6b00412 CrossRefGoogle Scholar
  14. Website: http://Chemoth.com. Accessed 03 Oct 2017.

Copyright information

© Institute of Chemistry, Slovak Academy of Sciences 2018

Authors and Affiliations

  1. 1.Oncogen Pharma Sdn BhdShah AlamMalaysia

Personalised recommendations